GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons

Peripherally delivered glucagon-like peptide-1 (GLP-1)-based drugs suppress eating through their action in the brain. However, the specific neuronal mechanisms, especially their impacts on the orexigenic circuit, remain largely elusive. Neuropeptide Y (NPY) neurons in the nucleus tractus solitarius (NTS) are newly identified as orexigenic neurons with a potent eating-stimulating effect, but their responses to GLP-1 drugs are unknown. Through ex vivo electrophysiological recordings, we study the impacts of GLP-1 receptor (GLP-1R) agonist exendin-4 on NTS^NPY neurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTS^NPY neuronal activity via GABA_b receptors by augmenting presynaptic GABA release. We also explored the contribution of NTS^NPY neurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTS^NPY neurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTS^NPY neurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTS^NPY neurons that may be targeted by a GLP-1R agonist to suppress food intake, suggesting that this neuronal population has translational importance as a potential therapeutic target for obesity treatment.<b>NEW & NOTEWORTHY</b> This study discovers that the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 indirectly inhibits the majority of orexigenic hindbrain NPY neurons via GABA_b receptors by augmenting presynaptic GABA release. Chemogenetic activation of these NPY neurons effectively counteracts exendin-4 (Exn-4)-induced anorexigenic effect, whereas chemogenetic inhibition of them mimics the eating-suppressing effect of exendin-4. This study uncovers a mechanism by which Exn-4 inhibits orexigenic hindbrain NPY neurons, thereby providing new insights into how GLP-1 drugs suppress food intake.